细胞周期和凋亡调节蛋白 (CARP)-1 是一种新型的阿霉素诱导的弥漫性大 B 细胞淋巴瘤 (DLBL) 生长抑制剂。

Cell cycle and apoptosis regulatory protein (CARP)-1 is a novel, adriamycin-inducible, diffuse large B-cell lymphoma (DLBL) growth suppressor.

机构信息

Room B4334, Veterans Affairs Medical Center, Wayne State University, 4646 John R, Detroit, MI 48201, USA.

出版信息

Cancer Chemother Pharmacol. 2011 Jun;67(6):1401-13. doi: 10.1007/s00280-010-1442-6. Epub 2010 Aug 31.

DOI:10.1007/s00280-010-1442-6

PMID:20809119

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3809905/

Abstract

UNLABELLED

Diffuse large B-cell lymphoma (DLCL) accounts for 30-40% of adult non-Hodgkin's Lymphoma (NHL). Current anti-NHL therapies often target cellular growth suppression pathways and include R-CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone plus monoclonal anti-CD20 antibody rituximab). However, since many patients relapse, resistant cells to these therapies remain a significant problem and necessitate development of new intervention strategies. Cell cycle and apoptosis regulatory protein (CARP)-1 functions in a biphasic manner to regulate growth factor as well as chemotherapy (adriamycin, etoposide, or iressa)-dependent signaling.

PURPOSE

To determine whether CARP-1 is a novel suppressor of lymphoma growth.

METHODS

Flow cytometric analyses coupled with Western immunoblotting, cell growth, apoptosis, and immunocytochemistry methodologies were utilized to determine CARP-1-dependent lymphoma growth inhibition in vitro and in vivo.

RESULTS

CARP-1 expression correlated with activated caspase-3 and inversely correlated with activated Akt in DLCL. Exposure to adriamycin stimulated CARP-1 expression and inhibited growth of Raji cells, but not CHOP-resistant WSU-DLCL2 cells. Expression of wild-type CARP-1 or its apoptosis-inducing mutants inhibited growth of Raji as well as CHOP-resistant WSU-DLCL2 cells, in part by activating caspase-9 and apoptosis. Since CARP-1 harbors multiple, apoptosis-promoting subdomains, we investigated whether epigenetic compensation of CARP-1 function by intracellular delivery of trans-activator of transcription (TAT) domain-tagged CARP-1 peptide(s) will inhibit lymphoma growth. Treatments with TAT-tagged CARP-1 peptides suppressed growth of the Raji and WSU-DLCL2 cells by stimulating apoptosis. TAT-CARP-1 (1-198) as well as (896-1150) peptides also suppressed growth of WSU-DLCL2 cell-derived tumor xenografts in SCID mice, while administration of TAT-CARP-1 (1-198) also inhibited growth of WSU-FSCCL cell-derived ascites and prolonged host survival.

CONCLUSION

CARP-1 is a suppressor of NHL growth and could be exploited for targeting the resistant DLCL.

摘要

未标记

弥漫性大 B 细胞淋巴瘤 (DLCL) 占成人非霍奇金淋巴瘤 (NHL) 的 30-40%。目前的 NHL 治疗方法通常针对细胞生长抑制途径，包括 R-CHOP（环磷酰胺、阿霉素、长春新碱和泼尼松加单克隆抗 CD20 抗体利妥昔单抗）。然而，由于许多患者复发，对这些疗法有耐药性的细胞仍然是一个重大问题，需要开发新的干预策略。细胞周期和凋亡调节蛋白 (CARP)-1 以双相方式发挥作用，调节生长因子以及化疗（阿霉素、依托泊苷或易瑞沙）依赖性信号。

目的

确定 CARP-1 是否是一种新型的淋巴瘤生长抑制剂。

方法

流式细胞术分析结合 Western 免疫印迹、细胞生长、凋亡和免疫细胞化学方法，用于体外和体内确定 CARP-1 依赖性淋巴瘤生长抑制。

结果

CARP-1 的表达与活化的 caspase-3 相关，与 DLCL 中的活化 Akt 呈负相关。阿霉素暴露刺激 CARP-1 表达并抑制 Raji 细胞的生长，但不抑制 CHOP 耐药 WSU-DLCL2 细胞。野生型 CARP-1 或其诱导凋亡的突变体的表达抑制了 Raji 以及 CHOP 耐药 WSU-DLCL2 细胞的生长，部分通过激活 caspase-9 和凋亡。由于 CARP-1 含有多个促进凋亡的亚结构域，我们研究了通过细胞内递送电转蛋白 (TAT) 结构域标记的 CARP-1 肽是否可以抑制淋巴瘤生长来补偿 CARP-1 功能的表观遗传。用 TAT 标记的 CARP-1 肽处理可通过刺激凋亡来抑制 Raji 和 WSU-DLCL2 细胞的生长。TAT-CARP-1(1-198)和(896-1150)肽也抑制了 WSU-DLCL2 细胞衍生的异种移植肿瘤在 SCID 小鼠中的生长，而 TAT-CARP-1(1-198)的给药也抑制了 WSU-FSCCL 细胞衍生的腹水的生长并延长了宿主的存活时间。